KEYTRUDA® for locally advanced unresectable or metastatic esophageal cancer, in the first-line setting1
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EXPLORE KEYTRUDA® in the KEYNOTE-590 trial for patients with locally advanced unresectable or metastatic esophageal cancer
KEYNOTE-590 trial: Placebo-controlled trial of KEYTRUDA® for patients with locally advanced (not resectable or curable with radiation therapy) or metastatic esophageal carcinoma or esophagogastric junction adenocarcinoma, in the first-line setting. (Siewert Type 1)
Trial overview
- Randomized, multicenter, placebo-controlled trial
- Treatment arms were KEYTRUDA® in combination with cisplatin + fluorouracil and placebo in combination with cisplatin + fluorouracil
- Encompassed 749 patients with locally advanced unresectable or metastatic esophageal carcinoma or esophagogastric junction adenocarcinoma. (Siewert Type 1)
- PD-L1 testing required
- Patients with active autoimmune disease, a medical condition that required immunosuppression, known HER2 positive EGJ adenocarcinoma, or a history of prior treatment with an immune checkpoint inhibitor were ineligible
Treatment arms
KEYTRUDA® 200 mg on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle
– for up to six cyclesand fluorouracil (FU) 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.
Placebo on Day 1 of each three-week cycle in combination with cisplatin 80 mg/m2 IV on Day 1 of each three-week cycle
– for up to six cyclesand fluorouracil (FU) 800 mg/m2 IV per day on Day 1 to Day 5 of each three-week cycle, or per local standard for FU administration, for up to 24 months.
Primary endpoints
- Overall survival
- Progression-free survival, as assessed by investigator using RECIST 1.1
Secondary endpoints
- Objective response rate, as assessed by investigator using RECIST 1.1
- Duration of Response, as assessed by investigator using RECIST 1.1
CI=confidence interval; CPS=combined positive score; ESCC=esophageal squamous cell carcinoma; HR=hazard ratio; ITT=intent-to-treat; PD-L1=programmed death-ligand 1.
Overall Survival
Demonstrated Superior Overall Survival vs Placebo + Chemotherapy
27% risk of death reduction with KEYTRUDA® + cisplatin/5-FU (262/373 patients with event) vs. cisplatin/5-FU alone (309/376 patients with event) (HR=0.73; 95% CI: 0.62, 0.86; p<0.0001) (interim analysis) a,b
Kaplan-Meier Curve for Overall Survival in the KEYNOTE-590 trial (ITT Population)
a Based on the stratified Cox proportional hazard model.
b The corresponding p-value bounds at the interim analysis was 0.01421, following pre-specified multiplicity adjustment.Median in Months†
Median in months for Overall Survival for Patients with KEYTRUDA® + cisplatin/5-FU vs cisplatin/5-FU alone
KEYTRUDA®
+ cisplatin/5-FUPlacebo
+ cisplatin/5-FUmOS (months)† 12.4 (95%CI: 10.5, 14.0)9.8 (8.8, 10.8)Prespecified analyses of OS and PFS based on squamous cell histology, PD-L1 CPS ≥10, and all patients
Subgroup analyses of the results from the KEYNOTE-590 trial: PD-L1 CPS ≥10 subgroup
Overall Survival
38% improvement in overall survival (interim analysis) (HR: 0.62* [95% CI: 0.49, 0.78], p<0.0001#)
- KEYTRUDA® + cisplatin/5-FU: 124/186 with event
- placebo + cisplatin/5-FU: 165/197 with event
* Based on the stratified Cox proportional hazard
# The corresponding p-value bounds at the interim analysis for OS in ESCC PD‐L1 CPS ≥ 10, was 0.01414, following prespecified multiplicity adjustment.Median in months†
Median in months for Overall Survival for Patients with KEYTRUDA® + cisplatin/5-FU vs cisplatin/5-FU alone, PD-L1 CPS ≥10 subgroup (interim analysis)
KEYTRUDA® + cisplatin/5-FUPlacebo + cisplatin/5-FUmOS (months)† 13.5 (95%CI:11.1, 15.6)9.4 (8.0, 10.7)Subgroup analyses of results from the KEYNOTE-590 trial: ESCC with PD-L1 CPS ≥ 10 subgroup
Overall Survival
43% improvement in overall survival (interim analysis) (HR: 0.57‡ [95% CI: 0.43, 0.75], p<0.0001#)
- KEYTRUDA® + cisplatin/5-FU (94/143 with event)
- placebo + cisplatin/5-FU (121/143 with event)
‡ Based on the stratified Cox proportional hazard
# The corresponding p-value bounds at the interim analysis for OS in ESCC PD‐L1 CPS ≥ 10, was 0.0067, following prespecified multiplicity adjustment.Median in months†
Median in months Overall Survival for Patients with KEYTRUDA® + cisplatin/5-FU vs cisplatin/5-FU alone, ESCC with PD-L1 CPS ≥ 10 subgroup (interim analysis)
KEYTRUDA® + cisplatin/5-FUPlacebo + cisplatin/5-FUmOS (months)† 13.9 (95%CI:11.1, 17.7)8.8 (7.8, 10.5)CI=confidence interval; CPS=combined positive score; ESCC=esophageal squamous cell carcinoma; HR=hazard ratio; ITT=intent-to-treat; PD-L1=programmed death-ligand 1.
KEYTRUDA® demonstrated safety profile results in patients with locally advanced unresectable or metastatic esophageal cancer vs chemotherapy
The most common Grade 3-5 treatment-related adverse events were:
Adverse Reaction
KEYTRUDA® + cisplatin + FU
(n=370) %
Placebo + cisplatin + FU
(n=370) %Neutrophil count decreased22.716.7Anemia12.414.6Neutropenia14.316.3White blood cell count decreased8.64.8Nausea76.5Vomiting6.24.9Fatigue6.25.4Stomatitis5.73.8Hyponatremia5.45.4- Fatal trAEs occurred in 2.4% of patients receiving KEYTRUDA® + chemotherapy
- Fatal trAEs included 1 case each of multiple organ dysfunction syndrome, pulmonary embolism, interstitial lung disease, pneumonitis, febrile neutropenia, pneumonia, acute kidney injury, diarrhea, and hepatic failure.
- Serious treatment-related adverse events occurred in 32% of patients receiving KEYTRUDA® in combination with chemotherapy
- Serious treatment-related adverse events in ≥ 2% of patients receiving KEYTRUDA® in combination with chemotherapy included: pneumonia (3.5%), pneumonitis (3.2%), febrile neutropenia (2.4%), acute kidney injury (2.2%), and vomiting (2.2%).
- KEYTRUDA® was discontinued for trAEs in 7.3% of patients.
- The most common trAEs resulting in discontinuation of KEYTRUDA® were pneumonitis/interstitial lung disease (2.2%), transaminase increased (0.6%), blood creatinine increased (0.5%), diarrhea (0.5%), infusion-related reaction (0.5%), hepatitis (0.3%), hepatic failure (0.3%), and acute kidney injury (0.3%).
Treatment-related adverse events (any grade) reported in ≥20% of patients were:
Adverse Reaction
KEYTRUDA® + cisplatin + FU
(n=370) %
Placebo + cisplatin + FU
(n=370) %Nausea6359.5Decreased appetite39.232.2Anemia38.643.8Fatigue36.528.9Neutrophil count decreased36.529.5Vomiting29.726.8Diarrhea26.223Neutropenia25.923.8Stomatitis25.925.1White blood cell count decreased24.118.6For the complete list of treatment-related adverse events, please consult the Product Monograph.
Consider KEYTRUDA® as part of your treatment regimen for your eligible patients with locally advanced unresectable or metastatic esophageal cancer.
CI=confidence interval; CPS=combined positive score; ESCC=esophageal squamous cell carcinoma; HR=hazard ratio; ITT=intent-to-treat; PD-L1=programmed death-ligand 1.
References:
1. Merck Canada Inc. KEYTRUDA® Product Monograph. April 19, 2023.
2. ASCO and OH (CCO) Joint Guideline Update. Available at: https://www.cancercareontario.ca/en/guidelines-advice/types-of-cancer/62681
3. Hanna, N et al. (2020). Therapy for Stage IV Non-Small-Cell Lung Cancer Without Driver Alterations: ASCO and OH (CCO) Joint Guideline Update. Journal of clinical oncology : official journal of the American Society of Clinical Oncology, 38(14), 1608–1632. https://doi.org/10.1200/JCO.19.03022
4. Rastogi M, et al. (2016). An unusual response with long term survival using erlotinib in NSCLC lung with brain metastases. BMJ Case Rep. bcr2015213239. https://doi.org/10.1136/bcr-2015-213239
5. Medline. Available at: https://medlineplus.gov/ency/imagepages/1183.htm
6. Dromain C, Beigelman C, Pozzessere C, Duran R, Digklia A. Imaging of tumour response to immunotherapy. Eur Radiol Exp. 2020 Jan 3;4(1):2.
CA-PDO-00148